Chronic Renal Failure

Department of Nephrology, The First Affiliated Hospital of Sun Yat-Sen University

Jiang Zongpei

CONTANT DEFINITIONS

ETIOLOGY

PATHOPHYSIOLOGY OF CKD

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA

CLINICAL MANIFESTATIONS OF CHRONIC RENAL

FAILURE

EVALUATION AND MANAGEMENT OF PATIENTS WITH

CKD

TREATMENT

DEFINITIONS • Chronic Kidney disease (CKD) :

CKD is a pathophysiologic process with multiple etiologies, resulting in the irreversible attrition of nephron number and function, frequently leading to end stage renal disease (ESRD).

• ESRD

represents a clinical state or condition in which there has been an irreversible loss of renal function, and these patients usually need to accept renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia.

• Uremia

Uremia is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or undertreated acute or chronic renal failure.

Major causes of chronic renal failure • Glomerulopathies Primary glomerular diseases: 1. Focal and segmental glomerulosclerosis(FSGS) 2. Membranoproliferative glomerulonephritis(MPGN) 3. IgA nephropathy(IgAN) 4. Membranous nephropathy(MN)

Secondary glomerular diseases: 1.Diabetic nephropathy 2.Lupus nephropathy 3. Post-infectious glomerulonephritis 4. Amyloidosis 5.HIV-associated nephropathy 6.Collagen-vascular diseases 7.Sickle cell nephropathy 8. HIV associated membranoprolifer

ative glomerulonephritis

• Tubulointerstitial nephritis1. Drug hypersensitivity2. Heavy metals3. Analgesic nephropathy4. Reflux/chronic pyelonephritis5. Idiopathic• Hereditary diseases1. Polycystic kidney disease2. Medullary cystic disease3. Alport’s syndrome• Obstructive nephropathies1. Prostatic disease2. Nephrolithiasis3. Retroperitoneal fibrosis/tumor4. Congenital• Vascular diseases1. Hypertensive nephrosclerosis2. Renal artery stenosis

ETIOLOGY

The leading underlying etiologies of both CKD and ESRD in China.

• Glomerulonephritis 60%• Diabetic nephropathy 20%• Lupus nephropahty 5-10%• Hypertensive nephrosclerosis 5-10%• Others 5-10%

PATHOPHYSIOLOGY OF CKD The pathophysiology that why CKD progress to ESRD is unclearly now.

vasoactive moleculesCytokines

growth factorsRenin-angiotensin axis

glomerular hyperperfusion,Hypertensionhyperfiltration

glomerular hypertrophy

sclerosis

nephron population decrease and reduction of renal mass.

Such reduction of renal mass causes structural and functional hypertrophy of surviving ne

phrons

1

Renal pathologic change in CRF

Normal Sclerosis

Stages of chronic kidney disease: A clinical action plan

Stage Description GFR Action symptom

1 Kidney damage with normal of ↑GFR

≥90 Diagnosis and treatment.

Treatment of basic diseases.

Slowing of progression. Cardiovascular disease risk reduction.

patients often remain free of symptom

2 Kidney damage with mildly↓GFR

60-89 Estimating progression

3 Moderately↓GFR 30-59 Evaluating and treating complications

clinical and laboratory complications of CKD become progressive4 Severely↓GFR 15-29 Preparation for kidney repl

acement therapy.

5 Kidney failure <15 Replacement (if uremia is present)

Uremic symptoms become prominent and usually the patients need to accept renal replacement therapy

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA

• Which toxin is responsible for uremic symptoms remain unclear.

• Urea may contribute to some of the clinical abnormalities, including

anorexia, malaise, vomiting, and headache.

• Nitrogenous excretory products (guanido compounds, urates and s

o on) and nitrogenous compounds (so-called middle molecules tox

ins) are associated with neuromuscular abnormalities and believed

to contribute to morbidity and mortality in uremic subjects.

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA

• A host of metabolic and endocrine functions normally subserved

by the kidney are also impaired, resulting in anemia; malnutritio

n; impaired metabolism of carbohydrates, fats, and proteins and

metabolic bone disease.

• The endocrine hormone involved in ESRD patients are PTH, ins

ulin, erythropoietin (EPO) and so on.

CLINICAL MANIFESTATIONS OF CHRONIC

RENAL FAILURE

• Uremia leads to disturbances in the function of every organ system.

• The symptoms of chronic renal failure often develop slowly and are nonspecific.

• Individuals can remain asymptomatic until renal failure is far-advanced (GFR<10-15 ml/min).

CLINICAL MANIFESTATIONS OF CHRONIC RENAL FAILURE

• FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS

• BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM

• CARDIOVASCULAR ABNORMALITIES

• HEMATOLOGIC ABNORMALITIES

• NEUROMUSCULAR ABNORMALITIES

• GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIES

• ENDOCRINE METABOLIC DISTURBANCES

FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS

Sodium And Water Homeostasis

• In most patients with stable CKD, the total body contents of Na+ and H2

O are increased modestly, and will cause edema and hypertention.

Glomerulo-tubular balance impaired and promote Na+ retention

Na+ retention may lead to cumulative positive Na+ balance and cause ext

racellular fluid volume (ECFV) expansion.

• Patients with CKD also have impaired renal mechanisms for conserving

Na+ and H2O. And these patients are easy to appear volume depletion.

FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS

Potassium Homeostasis In CKD

hyperkalemia is common in CKD patients dietary intake, protein catabolism, hemorrhage, transfusion of stored

red blood cells, metabolic acidosis ACE inhibitors and angiotensin receptor blockers(ARB), and some di

uretics

Hypokalemia is uncommon in CKD usually caused by markedly reduced dietary K+ intake Or association with excessive diuretic therapy or gastrointestinal loss

es. And also be seen in tubulointerstitial diseases, such as Fanconi’s syn

drome, renal tubular acidosis

FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS

Metabolic Acidosis is a common disturbance during the advanced stage

s of CKD

Reduced ability to produce ammonia.

Hyperkalemia further depresses urinary ammonium excretion.

BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM

The disorders of calcium, phosphorus, and bone diseases i

s common in CKD.

The major disorders of bone disease can be classified into:

1. high bone turnover with high PTH levels (including osteitis f

ibrosa)

2. low bone turnover with low or normal PTH levels (osteomal

acia and adynamic bone disease).

BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM

• The most common disorder is osteitis fibrosa.

As GFR decreases below 25% of normal

phosphorus excretion is impaired

Hyperphosphatemia

hypocalcemia

stimulating secretion of PTH

“secondary hyperparathyroidism”

high bone turnover with osteitis fibrosa.

Decreased renalFunction

Decreased 1.25(oh)2D3

A13+ IntoxicationAccumulation ofβ2 microglobulinHyperphosphatemia

Decreased ionizedCa2+

HyperparathyroidismDecreasedexpressionof calcium-

sensingreceptor

HyperplasiaOf the

parathyroidglands

Osteitis fibrosa cystica(high-turnover bone disease)

Osteomalacia Adynamic bonedisease

Dialysis-relatedamyloidosis

Metabolic acidosis Excess Ca and vit D,PD,diabetes

CARDIOVASCULAR ABNORMALITIES

• Cardiovascular disease is the leading cause of morbidity and mortality in patients with CKD at all stages.

Ischemic Cardiovascular Disease

Congestive Heart Failure

Hypertension And Left Ventricular Hypertrophy

Pericarditis

Ischemic Cardiovascular Disease • CKD is a major risk factor for ischemic cardiovascular disease, inclu

ding coronary heart, cerebrovascular, and peripheral vascular diseases

• Ischemic cardiovascular disease in CKD caused by both traditional risk factors and CKD-related risk factors

The traditional risk factors include hypertension, hypervolemia, dyslipidemia, and so on.

The CKD-related risks include anemia, hyperphosphatemia, high PTH level, and a state of “microinflammation” that can be found at all stages of CKD.

Hypertension And Left Ventricular

Hypertrophy • Hypertension is the most common complication of CKD and ESRD.

It may develop early during the course of CKD

Volume overload is the major cause of hypertension in uremia.

Rarely, Patients may develop malignant hypertension

• Left ventricular hypertrophy and dilated cardiomyopathy are the mos

t important risk factors for cardiovascular morbidity and mortality in p

atients with CKD and ESRD

thought to be related prolonged hypertension and ECFV overload.

anemia

Toxins in uremia

Congestive Heart Failure

Abnormal cardiac function

secondary to myocardial ischemic disease

and/or left ventricular hypertrophy

together with salt and water retention in uremia

often result in congestive heart failure and/or pulmonary edema.

These patients usually need to accept dialysis treatment

immediately.

Pericarditis

• Pericarditis is common in ESRD patients. And usually indicate the patients need accept hemodialysis immediately.

Pericardial pain with respiratory accentuation, accompanied by a friction rub, are the hallmarks of uremic pericarditis.

The finding of a multicomponent friction rub strongly supports the diagnosis.

Classic electrocardiographic and echocardiography is useful in diagnosis for pericarditis.

HEMATOLOGIC ABNORMALITIES

Anemia • Anemia in CKD is a normocytic, normochromic

• And will observed beginning at stage 3 CKD and is almost univ

ersal at stage 4.

• the anemia of CKD is associated with a number of physiologic

abnormalities

decreased tissue oxygen delivery and utilization

increased cardiac output

cardiac enlargement

ventricular hypertrophy

congestive heart failure

impaired body defense against infection.

HEMATOLOGIC ABNORMALITIES Anemia

The primary cause of anemia in patients with CKD

insufficient production of EPO by the diseased kidneys.

iron and folate deficiency

Severe PTH

acute and chronic inflammation

aluminum toxicity

shortened red cell survival.

NEUROMUSCULAR ABNORMALITIES

• Central, peripheral, and autonomic neuropathy, as well as abnorm

alities in muscle composition and function, are all common compli

cations in CKD.

• Retained nitrogenous metabolites and middle molecules toxins as

well as PTH , all contribute to the pathophysiology of neuromuscu

lar abnormalities.

• The “restless legs syndrome ” is characterized by illdefined sensat

ions of discomfort in the legs and legs and feet requiring frequentl

y movement.

GASTROINTESTINAL AND NUTRITIONAL

ABNORMALITIES

Gastrointestinal symptoms (abdominal pain, nausea, vomiting)

usually may the first symptom for ESRD patients.

Urimic toxins is associated with an unpleasant metallic taste s

ensation in ESRD patient.

Gastritis, peptic disease are common in ESRD patient.

Protein restriction is useful in diminishing the symptoms. But it

is sometimes easy to cause malnutrition.

ENDOCRINE-METABOLIC

DISTURBANCES

• Disturbances in parathyroid function

• Glucose metabolism impaired in CKD

Because the kidney contributes significantly to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic subjects.

Many hypoglycemic drugs require dose reduction in renal failure

• The growth and sex hormone secretion is impaired in CKD ,

Sexual maturation is often in children with CKD.

EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD History Hypertension Diabetes systemic infectious Inflammatory metabolic diseases exposure to drugs and toxins a family history of renal and urologic disease.

In evaluating the uremic syndrome questions about appetite； diet； nausea； vomiting； edema；

weight change

Physical examination blood pressure examination of the abdomen for renal masses, examination for edema neurologic examination

EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Laboratory Investigations

Laboratory investigation should focus on to find evidence to unde

rlying disease process and its continued activity.

immunologic tests (SLE and vasculitis)

Serum and uriary protein electrophoresis.

Urinalysis, a 24h urine collection for protein excretion

measurements of plasma creatinine and estimation of GFR.

to assess metabolic bone disease

hemoglobin.

EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Imaging Studies

The most useful imaging study is renal ultrasonography. Provide an estimate of kidney size and obstructive uropathy. The small kidneys usually supports the diagnosis of progressive

CKD is irreversible Normal kidney size usually suggests the possibility of an acute ra

ther than chronic process.

a vascular imaging procedure, such as doppler sonography of the renal arteries, radionuclide scintigraphy, magnetic resonance angiography (MRA)

EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Renal Biopsy

Renal biopsy should be reserved for patients with near normal kidney size, in whom a definitive diagnosis cannot be made yet.

Contraindications to renal biopsy include:

bilateral small kidneys

polycystic kidney disease

uncontrolled hypertension

urinary tract or perinephric infection

bleeding diathesis

respiratory distress

morbid obesity.

ESTABLISHING THE DIAGNOSIS AND ETIOLOGY OF CKD

The most important initial step in the evaluation of a patient presenting with renal failure is to distinguish newly diagnosed CKD from acute renal failure.

the demonstration of evidence of chronic renal failure

Hyperphosphatemia

Hypocalcemia

elevated PTH levels

normocytic and normochromic anemia

bilaterally reduced kidney size(<8.5 cm)

Reversible causes of renal failure

Reversible factors Diagnostic clues

Infection Urine culture and sensitivity tests

Obstruction Bladder catheterization, then renal ultrasound

Extracellular fluid volume depletion

Orthostatic blood pressure and pulse:↓blood pressure and ↑pulse upon sitting up from a supine position

Hypokalemia, hypercalcemia, and hyperuricemia(usually >15 mg/dL)

Serum electrolytes, calcium, phosphate

uric acid

Nephrotoxic agents Drug history

Hypertension Blood pressure, chest X-ray

Congestive heart failure Physical examination, chest X-ray

TREATMENT • SLOWING THE PROGRESSION OF CKD Protein Restriction Reducing Intraglomerular Hypertension And Proteinuria

• MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Disorders of Mineral Metabolism Hypertension Cardiovascular Disease Uremic Pericarditis Congestive Heart Failure Anemia Abnormal Hemostasis Renal replacement therapy

SLOWING THE PROGRESSION OF CKD Protein Restriction

• A major goal of protein restriction in CKD, is to slow the progression of nephron injury.

• Protein restriction should be carried out in the context of an overall dietary program that keeping nutritional status and avoids malnutrition.

• Metabolic and nutritional studies indicate that protein requirements for patients with CKD are in the range of 0.6-0.8 g/kg per day.

• And we need give patients enough essential amino acids and energy supply (35 kcal/kg per day).

SLOWING THE PROGRESSION OF CKD Reducin

g Intraglomerular Hypertension And Proteinuria • Progressive renal injury in CKD appears to be most closely related

to the height of intraglomerular pressure and/or the extent of glomerular hypertrophy.

• Antihypertensive therapy in patients with CKD also aims to slow the progression of nephron injury, by reduce intraglomerular hypertension and hypertrophy.

• ACE inhibitors(ACEI) and angiotensin receptor blockers (ARB) are now clearly established as effective, antiproteinuric and anti-intraglomerular hypertension agents.

• If patients present side effects of the use of ACEI/ARBthese (e.g. cough, hyperkalemia) . We may choice of calcium channel blockers (CCB) as a second line medicine.

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Disorders of Mineral Metabolism

• Treatment should begin with dietary phosphorus restriction to

<1000 mg/d. Oral phosphorus binding agents.

• Vitamin D or vitamin D analogs should be given when PTH level

is more than two to three times to normal

• It is particularly important to maintain the calcium-phosphate

product in the normal range to avoid metastatic calcification.

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Hypertension

• Volume control with salt restriction is the essential of therapy.

• The choice of antihypertensive agent is similar to that in the general population, ACE inhibitior, ARB, CCB, or combination.

• In all patients with CKD, blood pressure should be controlled to at least the level of 130/80 to 85mmHg.

• In CKD patients with diabetes or proteinuria > 1g per 24 h, blood pressure should be further reduced to 125/75 mmHg.

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Cardiovascular Disease

Risk factor Life-style changes

Hyperlipidemia

Hypertension

CKD related risk factor

Congestive Heart Failure Water and salt intake

Diuretics

Digoxin

ACE inhibitors ARB

Dialysis immediately

Uremic Pericarditis Dialysis immediately

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE Anemia

• As insufficient production of EPO by the diseased kidneys,

recombinant human EPO is most important in treatment of

anemia caused by kidney diseases.

• The iron status of the patient with CKD must be assessed, and

adequate iron stores should be available before treatment with

EPO

Management guidelines for correction of anemia of chronic renal disease

Erythropoietin

Starting dosage: 50-150 units/kg per week IV or SC (once, twice, or three times per week )

Target hemoglobin(Hb): 11-12 g/dL

Optimal rate of correction Increase Hb by 1-2 g/dL over 4-week period

Darbepoetin alfa

Starting dosage: 0.45 ug/kg administered as a single IV or SC injection once weekly 0.75 ug/kg administered as a single IV or SC injection once every 2 Weeks

Target Hb: ≤12 g/dL

Optimal rate of correction Increase Hb by 1-2 g/dL over 4-week period

Iron

1. Monitor iron stores by percent transferrin saturation (TSat) and serum ferritin.

2. If patient is iron-deficient (Tsat <20%; serum ferritin<100 ug/L, administer iron, 50-100 mg IV twice per week for 5 weeks; if iron are still low, repeat the same course.)

3. If iron indices are normal yet Hb is still inadequate, administer IV iron as outlined above; monitor Hb, Tsat, and ferritin.

4. Withhold iron therapy when TSat >50% and/or ferritin >800 ng/mL(>800 ug/L).

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE RENAL REPLACEMENT THERAPY

• GFR is below 10 ml/min in CRF usually need to require renal replacement therapy.

• Absolute indications for dialysis include: severe volume overload, especially in heart failure severe hyperkalemia and/or acidosis encephalopathy not otherwise explained pericarditis or other serositis symptomatic uremia (e.g., anorexia, nausea, vomiting) protein energy malnutrition.

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE

Hemodialysis

• Hemodialysis requires a constant flow of blood along one side of a semipermeable membrane, and with dialysate solution along the other side. Diffusion and convection allow the dialysate to remove unwanted substances from the blood while adding back needed components.

• Most patients undergo dialysis thrice weekly, usually for 3-4 h.

Peritoneal dialysis is through a peritoneal catheter that allows infusion of a dialysate solution into the abdominal cavity, which allows transfer of solutes across the peritoneal membrane.

Patients generally have the choice of performing their own exchanges (2-3 L of dialysate, 4-5 times during daytime hours) or using an automated device at night. The most common complication of peritoneal dialysis is peritonitis.

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILURE

Peritoneal dialysis

Up to 50% of all patients with ESRD are su

itable for kidney transplantation.

The most common method for kidney trans

plantantion is put the graft in right side plev

ic cavity.

Two-thirds of kidney transplants come fro

m deceased donors, and the others from li

ving related or unrelated donors.

Immunosuppressive drugs developed very

fast in these years. (Cyclosporine, MMF, t

acrolimus and rapamycin.)

MANAGING COMPLICATIONS OF CHRONIC RENAL FAILUREkidney transplantation.

Conclusion DEFINITIONS

ETIOLOGY

PATHOPHYSIOLOGY OF CKD

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA

CLINICAL MANIFESTATIONS OF CHRONIC RENAL

FAILURE

EVALUATION AND MANAGEMENT OF PATIENTS WITH

CKD

TREATMENT

Thanks for your attention!